WO 2004/080492 discloses a method of radiofluorination of a vector which comprises reaction of a compound of formula (I) with a compound of formula (II):
or a compound of formula (III) with a compound of formula (IV)
wherein:                R1 is an aldehyde moiety, a ketone moiety, a protected aldehyde such as an acetal, a protected ketone, such as a ketal, or a functionality, such as diol or N-terminal serine residue, which can be rapidly and efficiently oxidised to an aldehyde or ketone using an oxidising agent;        R2 is a group selected from primary amine, secondary amine, hydroxylamine, hydrazine, hydrazide, aminoxy, phenylhydrazine, semicarbazide, and thiosemicarbazide and is preferably a hydrazine, hydrazide or aminoxy group;        R3 is a group selected from primary amine, secondary amine, hydroxylamine, hydrazine, hydrazide, aminoxy, phenylhydrazine, semicarbazide, or thiosemicarbazide, and is preferably a hydrazine, hydrazide or aminoxy group;        R4 is an aldehyde moiety, a ketone moiety, a protected aldehyde such as an acetal, a protected ketone, such as a ketal, or a functionality, such as diol or N-terminal serine residue, which can be rapidly and efficiently oxidised to an aldehyde or ketone using an oxidising agent;to give a conjugate of formula (V) or (VI) respectively:        
                wherein X is —CO—NH—, —NH—, —O—, —NHCONH—, or —NHCSNH—, and is preferably —CO—NH—, —NH— or —O—; Y is H, alkyl or aryl substituents; andthe Linker group in the formulae (II), (IV), (V) and (VI) is selected from:        
wherein n is an integer of 0 to 20; m is an integer of 1 to 10; p is an integer of 0 or 1; Z is O or S.
WO 2006/030291 discloses a method for radiofluorination comprising reaction of a compound of formula (I):
wherein the vector comprises the fragment:
with a compound of formula (II):
wherein:n is an integer of 0 to 20;m is an integer of 0 to 10;Y is hydrogen, C1-6alkyl, or phenylto give a compound of formula (III):
wherein m, n, and Y are defined as for the compound of formula (II) and the vector is as defined for the compound of formula (I).
Glaser et at [Bioconj. Chem., 19(4), 951-957 (2008)], describe the synthesis of 18F-labelled aldehydes, including 18F-fluorobenzaldehyde, and their conjugation to amino-oxy functionalised cyclic RGD peptides.
Speranza et at [Appl. Rad. Isotop., 67, 1664-1669 (2009)] describe an automated synthesis of [18F]-fluorobenzaldehyde ([18F]-FBA) using a TRACERlab™ apparatus. A hand-made purification device is used to purify the [18F]-FBA. Speranza et at describe the fact that cartridge purification is preferred over HPLC purification for automated synthesizer apparatus syntheses. Their cartridge methodology, however, suggests that dichloromethane or chloroform are the best solvents for [18F]-FBA purification. Both solvents have unsuitable toxicological properties for in vivo use, and are immiscible with water. The method is therefore unsuitable for radiopharmaceutical preparations.
Battle et at [J. Nucl. Med., 52(3), 424-430 (2011)] disclose monitoring anti-angiogenic therapy with [18F]-fluciclatide:

Battle et at mention that the [18F]-FBA used was purified by diluting with water, and trapping on a solid-phase extraction (SPE) cartridge. Impurities such as precursor, DMSO, Kryptofix-222 and hydrophilic by-products were said to be eluted to waste, and the [18F]-FBA subsequently eluted with ethanol. The present inventors have, however, found that using a C18 SPE cartridge only some of the precursor is eluted to waste, and the remainder co-elutes when the [18F]-FBA is eluted with ethanol.
There is therefore still a need for alternative methods of labelling biological targeting moieties with 18F.
The Present Invention.
The present invention provides improved 18F-radiolabelled biological targeting moiety (BTM) compositions, derived from the conjugation of 18F-labelled aldehydes. To aminooxy- or hydrazine-functionalised BTMs. The invention is based on detailed analyses of the impurities present in such aldehydes, and an understanding of how they may be carried through into the radiolabelled BTM product—plus how best to suppress all undesired impurity species. Many of these impurities were not recognised in the prior art, and hence such prior art agents contained undesirable species which would adversely affect the imaging characteristics.
In addition, the improved compositions of the present inventions can be achieved in shorter preparation times, which minimises any loss of 18F (half-life 109 minutes) radioactive content during the preparation and purification steps prior to use. The compositions of the present invention can be obtained using methodology which is amenable to automation on a commercial automated synthesizer apparatus—an advantage over prior art HPLC methods (which cannot be automated in this way). Automation confers improved reproducibility, as well as reduced operator radiation dose.
In addition, the higher radiochemical yield and purity of the product means that less functionalised BTM need be used in obtain the same amount of radioactive product. Since the unlabelled BTM will compete for the same biological site in vivo, lowering the amount of functionalised BTM present helps preserve the efficacy of the radiolabelled product. In addition, since the BTM may be e.g. a complex polypeptide or protein which is expensive and time-consuming to obtain, that is an important efficiency of time/materials.
The present invention provides compositions wherein the concentration of the desired 18F-radiofluorinated BTM is enhanced by a factor of about 40, while the chemical impurities are reduced by about 99% (ie. by a factor of about 100).